Inhibiting CBX4 efficiently suppress YAP nucleus translocation in hepatocellular carcinoma cells to protect against sorafenib resistance

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Abstract Background The discovery of biomarkers that predict the response to sorafenib and increase the efficiency of drug therapy represents a clinical challenge. This study aimed to investigate the possible role of inhibiting CBX4 to deregulate of CSCs and to evaluate the contribution of these molecules to sorafenib resistance in advanced HCC. Methods HCC cell lines and a xenograft mouse model with resistance to sorafenib were employed to analyze the effects of miR424 on CSC characteristics. RNA expression was analyzed by RT-PCR and next-generation sequencing in a cohort of 106 HCC cancer patients and sorafenib-resistant (SR) cell lines, respectively, to validate the key microRNAs and targets in the network. CBX4 expression was determined in HCC cells to examine YAP1-mediated stem-cell-like activation and its association with sorafenib resistance. Results MicroRNA and mRNA profiles of SR cell lines identified miR424 and its direct target CBX4 as significantly associated with stem-cell-like properties, poor survival and clinical characteristics. Functional experiments demonstrated that miR424 suppressed CBX4, and CBX4 induced nuclear translocation of YAP protein but was not associated with protein production. When YAP1 and CBX4 were modulated either alone or together in SR tumors with CA3 and UNC3866, respectively, tumorigenicity and stem-like properties were extremely inhibited, thus indicated that these compounds exerted a strong antitumor effect in vivo against SR HCC cells. Conclusions Our results revealed that blocking the crosstalk between CBX4 and YAP1 is critical in response to sorafenib resistance, and it could be a promising therapeutic strategy for patients with advanced HCC.

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